The ER UDPase ENTPD5 Promotes Protein N-Glycosylation, the Warburg Effect, and Proliferation in the PTEN Pathway
The ER UDPase ENTPD5 Promotes Protein N-Glycosylation, the Warburg Effect, and Proliferation in the PTEN Pathway
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DOI：
10.1016/j.cell.2010.10.010
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发表时间：
2010-11-24
期刊：
影响因子：
64.5
通讯作者：
Wang, Xiaodong
中科院分区：
文献类型：
--
作者：
Fang, Min;Shen, Zhirong;Wang, Xiaodong
PI 3 K和PTEN脂质磷酸酶控制细胞磷脂酰肌醇（3，4，5）-三磷酸的水平，磷脂酰肌醇（3，4，5）-三磷酸是促进细胞生长和存活的AKT激酶的激活剂。激活AKT的突变通常在人类癌症中观察到。我们在这里报告，ENTPD 5，内质网（ER）酶，是上调的细胞系和原发性人类肿瘤样本与活性AKT。ENTPD 5将UDP水解为UMP以促进蛋白质N-糖基化和ER中的折叠。PTEN缺失细胞中ENTPD 5的敲低导致ER应激和生长因子受体的丧失。ENTPD 5与胞苷一磷酸激酶-1和腺苷酸激酶-1一起构成ATP水解循环，将ATP转化为AMP，导致有氧糖酵解的补偿性增加，称为瓦尔堡效应。PTEN缺失细胞的生长在体外和小鼠异种移植肿瘤模型中都受到抑制。因此，ENTPD 5是PI 3 K/PTEN调节环的组成部分，也是抗癌治疗的潜在靶点。
PI3K and PTEN lipid phosphatase control the level of cellular phosphatidylinositol (3,4,5)-trisphosphate, an activator of AKT kinases that promotes cell growth and survival. Mutations activating AKT are commonly observed in human cancers. We report here that ENTPD5, an endoplasmic reticulum (ER) enzyme, is upregulated in cell lines and primary human tumor samples with active AKT. ENTPD5 hydrolyzes UDP to UMP to promote protein N-glycosylation and folding in ER. Knockdown of ENTPD5 in PTEN null cells causes ER stress and loss of growth factor receptors. ENTPD5, together with cytidine monophosphate kinase-1 and adenylate kinase-1, constitute an ATP hydrolysis cycle that converts ATP to AMP, resulting in a compensatory increase in aerobic glycolysis known as the Warburg effect. The growth of PTEN null cells is inhibited both in vitro and in mouse xenograft tumor models. ENTPD5 is therefore an integral part of the PI3K/PTEN regulatory loop and a potential target for anti-cancer therapy.